Novel inhibitors of polymorphonuclear neutrophil (PMN) elastase and cathepsin G: evaluation in vitro of their potential for the treatment of inflammatory connective tissue damage.
Inhibitors of neutrophil proteases may have therapeutic effects in inflammatory diseases. MDL 27,324 (Dansyl-Ala-Ala-Pro-Val-CF3), inhibits human neutrophil elastase and MDL 27,399 (MeOSucc-Ala-Ala-Pro-Phe-COOCH3), inhibits human neutrophil cathepsin G. These compounds individually or in combination, partially inhibited the hydrolysis of fluoresceinated bovine serum albumin and fluoresceinated immune complexes by rat and human neutrophil granule lysate. In contrast, the combination of inhibitors completely prevented the breakdown of a complex connective tissue substrate, azure hide powder. Rat neutrophils phagocytosed and hydrolyzed fluoresceinated immune complexes, a process which was inhibited by cytochalasin B (15 micrograms/ml, 65% inhibition) and chloroquine (200 microM, 80% inhibition). Although MDL 27,324 was taken up by the cells, it had only a modest inhibitory effect on the proteolysis of ingested fluoresceinated immune complexes (200 microM, 20% inhibition); MDL 27,399 had similar limited efficacy. Therefore, these compounds may be effective inhibitors of neutrophil serine proteases secreted into the extracellular space during inflammation without interfering with the normal process of intracellular degradation of phagocytosed material.
Doherty
N S
NS
Merrell Dow Research Institute, Cincinnati, Ohio 45215.
Dinerstein
R J
RJ
Mehdi
S
S
D000595:Amino Acid Sequence; D000818:Animals; D056649:Cathepsin G; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D003240:Connective Tissue Diseases / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000201:enzymology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D012697:Serine Endopeptidases
D009842:Oligopeptides; C067585:MDL 27324; C067586:MDL 27399; D002403:Cathepsins; D012697:Serine Endopeptidases; C534094:CTSG protein, human; D056649:Cathepsin G; C534097:Ctsg protein, rat; D010196:Pancreatic Elastase